Esters of 4-aminomethyl benzoic acid

ABSTRACT

NEW COMPOUNDS OF THE GENERAL FORMULA   1-(ARYL-OOC-),4-(H2N-CH2-)BENZENE   WHEREIN &#34;ARYL&#34; IS A PHENYL GROUP WHICH MAY HAVE ONE OR MORE SUBSTITUENTS SELECTED FROM HYDROXY, HALOGEN, NITRO, AMINO, CARBOXYL, FORMYL, SULFAMOYL, CARBOXYALKYLAMINO, C1 TO C6-ALKYL, C1 TO C6-ALKOXY, C1 TO C6-ALKENYL, PHENYL, CARBOXYALKYL, CARBOXYALKENYL, CARBOXYALKYLCARBONYL, HYDROXYALKYL, ALKOXYCARBONYL, AND CARBOXYALKYL THE ALKYL PORTION OF WHICH MAY BE SUBSTITUTED WITH AMINO. HYDROXY OR HALOGEN, AND THE PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF HAVE BEEN FOUND TO BE USEFUL AS HAVING ANTI-PLASMIN AND ANTI-FIBRINOLYTIC ACTIVITIES WITHOUT ANY ILL EFFECT AGAINST WARM-BLOOD ANIMALS. THE METHOD FOR THEIR PREPARATION IS ALSO DISCLOSED.

United States Patent 3,793,292 ESTERS 0F 4-AMINOME'IHYL BENZOIC ACID Yuichi Yamamura, Osaka, Setsuro Fujii, Toknshima, Atsnji Okano and Miyoshu Hirata, Tokyo, Yasushi Abiko, Matsudo, Masato Inaoka, Funabashi, Reimei Moroi, Chiba, Masahiro Iwamoto and Shoichi Funabashi, Tokyo, and Takeo Naito, Ichikawa, Japan, assJignor to Daiichi Seiyaku Co., Ltd., Chuo-ku, Tokyo,

apan No Drawing. Original application Sept. 30, 1969, Ser. No. 862,512. Divided and this application Apr. 12, 1971, Ser. No. 133,398

Int. Cl. C07c 101/42 US. Cl. 260-471 R 10 Claims ABSTRACT OF THE DISCLOSURE New compounds of the general formula NHg-CHz-QCO o-in i wherein "Aryl is a phenyl group which may have one or more substituents selected from hydroxy, halogen, nitro, amino, carboxyl, formyl, sulfamoyl, carboxyalkylamino, C to (i -alkyl, C to C -alkoxy, C to C ealkenyl, phenyl, carboxyalkoxy, carboxyalkenyl, carboxyalkylcarbonyl, hydroxyalkyl, alkoxycarbonyl, and carboxyalkyl the alkyl portion of whicn may be substituted with amino, hydroxy or halogen, and the pharmaceutically acceptable salts thereof have been found to be useful as having anti-plasmin and anti-fibrinolytic activities without any ill effect against warm-blood animals. The method for their preparation is also disclosed.

This application is a division of application Ser. No. 862,512, filed Sept. 30, 1969, and now Pat. No. 3,699,- 149.

This invention relates to new esters of certain acids. More particularly, this invention is concerned with the new esters of trans-4-aminornethyl-cyclohexane-l-carboxylic acid (t-AMCHA) or 4-aminomethyl-benzoic acid (PAMBA) and their pharmaceutically acceptable salts and the process for producing same, said esters and salts having distinguished anti-plasmin activity.

Heretofore, trans-4-aminomethyl-cyclohexane-l-carboxylic acid (cf. Chemical and Pharmaceutical Bulletin vol. 13, 1012-1014 (1965)) and its n-hexyl ester (cf. Japanese Pat. No. 507,331) or benzyl ester (cf. Japanese Pat. No. 526,594) have been known as those having antiplasmin activity. Among these, t-AMCHA has been used clinically with successful results. However, its n-hexyl and benzyl esters have not been used in practice because of their indistinct effectiveness over t-AMCHA and their unfavorable side effect.

We have now found that the new aromatic esters of t-AMCHA and PAMBA are efiective many times in antiplasmin activity over t-AMCHA and its n-hexyl and benzyl esters.

Compounds of the present invention are represented by the general formula:

wherein Q represents a trans-4-aminomethyl-cyclohexyl or 4-aminomethyl-phenyl group, and Aryl represents an aromatic group selected from phenyl, pyridyl, N-oxide-pyridyl and naphthyl groups which may have one or 31,793,292 Patented Feb. 19, 1974 more substituents. More specifically, the present invention comprehends compounds of the following two groups defined by the formula NHz-CHrQ-C o O-Aryl Nm-onc o O-Aryl wherein Aryl has the same meaning as above.

Compounds of the present invention which are new esters of t-AMCHA and PAMBA are valuable as medicines because of their distinguished anti-plasmin activity. The excellent activity of these esters can be considered owing to the existence of a direct ester linkage of an aromatic ring with the carboxyl group of t-AMCHA or PAMBA, without depending on the type and number of any substituents on said aromatic ring.

Accordingly, the aromatic group which is indicated by the symbol Aryl in the above-referred general formulas may have one or more (i.e. up to three) substituents selected from hydroxy, halogen, nitro, subst. or non-subst. amino, carboxyl, formyl, sulfamoyl, prim.-, sec.- or ter.- alkyl having 1-6 carbon atoms, alkoxy having 1-6 carbon atoms, alkenyl having 1-6 carbon atoms, phenyl, carboxyalkoxy, carboxyalkenyl, alkoxycarbonyl, carboxyalkylcarbonyl, hydroxyalkyl, and carboxyalkyl the alkyl portion of which may be substituted with amino, hydroxy or halogen.

Thus, it should be understood that the term, aryl, used in the specification and claims means to cover phenyl, pyridyl, N-oxide-pyridyl and naphthyl which may be optionally substituted with one or more of the abovesaid substituents.

The new aryl esters of the present invention can be prepared by the reaction of trans-4-aminomethylcyclohexane-l-carboxylic acid halogenide or 4-aminomethylbenzoic acid halogenide with an appropriate aryl alcohol. The amino group of these reactants may optionally be blocked by a protective group which is commonly used in a polypeptide synthesis. Such protective group can be easily removed after the intended reaction.

The typical preparation of compounds of the present invention can be illustrated by the following chemical formulas:

wherein Q means a aforementioned Q itself or that the terminal amino group of which is blocked with such protective group as benzyloxycarbonyl, tert-butoxycarbonyl and the like, and (Aryl)' means the aforementioned Aryl itself or that in which any amino and/ or carboxyl group if present are protected with benzyloxycarbonyl and/or benzyl group, respectively.

These protective group is Q and Aryl can be easily removed in above step of (1H) to (IV) by treating under reductive conditions or by hydrogen bromide-acetic acid.

The acid halogenide (I) may be directly reacted with the aryl alcohol (II) without using any solvent. Alternatively, the halogenide (I) is dissolved or suspended in a suitable inactive solvent such as ethyl acetate, benzene, tetrahydrofuran, dioxane, carbon tetrachloride, etc. and then the aryl alcohol (H) is added to the resulting soluand \I tion or suspension to eifect reaction. The reaction can proceed even at room temperatures. Stirring and heating are effective to have accelerated reaction. Use of an acidbinding agent, e.g. triethyl amine, pyridine or the like organic base, sometimes is recommendable.

Typical acid halogenides which are suitable as starting materials in this invention include trans-4-aminomethyl-cyclohexane-l-carbonyl chloride, 4-aminomethylbenzoyl chloride, trans-4-N-benzyloxycarbonylaminomethylcyclohexanel-carbonyl chloride, trans-4-N-tert.butyloxycarbonylaminomethyl-cyclohexane-l-carbonyl chloride, 4-N-benzyloxycarbonylaminomethyl-benzoyl chloride, 4-N-tert.-butyloxyoarbonyl-benzoyl chloride, trans-4-N-p-methoxybenzyloxycarbonylaminomethylcyclohexane-l-carbonyl chloride, etc.

The esterification reaction can be carried out by using a non-protected acid halide as the starting material if the aryl alcohol (II) used is liquid and the solubility of the resulting ester is sufficient to keep the reaction medium liquid.

However, when the aryl alcohol used is solid and has poor solubility into the organic solvent used, it is preferable to use a protected acid halide as the starting material for esterification, because the said protected acid halide (e.g. N-benzyloxycarbonyl-AMCHA-chloride) has considerable solubility to various organic solvents, while non-protected acid halides has little solubility.

Among these, those compounds in which the amino group is blocked are novel compounds and can be easily prepared by various methods which are known per so. For example, trans-4-aminomethyl-cyclohexane-l-carboxylic acid is brought into Schotten-Baumanns reaction with benzyloxycarbonyl chloride thereby to obtain trans-4-N- benzyloxycarbonyl-aminornethyl-cyclohexane 1 carboxylic acid (M.P. 115 1 17 C.), which is then reacted with thionyl chloride, phosphorus pentachloride, phosphorus trichloride, phosphorus oxychloride or the like chlorinating agent thereby to obtain hygroscopic crystalline trans- 4-N-benzyloxycarbonyl-aminomethyl cyclohexane-1-carbonyl chloride (M.P. 77-7 8 C.).

When the acid halogenide having a protective group in its amino group is employed as starting materials, the Compound (III) thereby obtained have the corresponding protective groups, which should be removed to obtain desired aryl ester (IV).

Removal of the protective group can be made by any conventionally known method, for example, (a) by treatrnent of an acetic acid solution of hydrobromic acid, or (b) by catalytic hydrogenation in the presence of palladium-carbon, platinum or the like catalyst in the absence or presence of an organic acid (e.g. p-toluene-sulfonic acid, succinic acid) methane sulfonic acid or an inor ganic acid (e.g. hydrochloride acid, hydrobromic acid, sulfuric acid) in hydrogen stream. When the hydrobromic acid-acetic acid solution is used, the intended reaction is conveniently carried out in the -35 hydrobromic acid solution at a temperature from room temperature to 100 C.

The procedure (a) is recommendable when only the acyl group for blocking amino group is to be removed with retaining any reduction-susceptible group (e.g. nitro, formyl, vinyl, etc.) on the aryl portion derived from the aryl alcohol reactant. If reduction of the reductionsusceptible group also should be efiected simultaneously with removal of the protective group, the catalytic hydrogenation (b) using palladium or platinum is recommendable.

As apparent from the above description, various steps can be taken suitably, depending on the type of desired aryl ester. It is appreciated that the most essential aspect of the present invention resides in finding of highly distinguished anti-plasmin activi y of Cfi new y esters- However, it also is to be noted that another aspect of the invention resides in the preparation of the said aryl esters by the reaction of trans-4-aminomethyl-cyclohexane 1 carbonyl halogenide or p-aminomethylbenzoyl halogenide with an appropriate aryl alcohol, whereas the introduction or removal of a protective group and the reduction or conversion of any aryl substituted or are more modifications of the invention which are obvious to those skilled in the art.

The thus obtained aryl esters of trans-AMCHA and PAMPA can be isolated in the conventional manner known per se. Usually, it is recommendable to recover these aryl esters in the form of their acid addition salts. Suitable salts are hydrochloride, hydrobromide sulfate, nitrate, phosphate, sulfonate, methanesulfonate, citrate, etc. Hydrochloride and methanesulfonate are particularly preferred because of their utility in medicinal applications.

The aryl esters and their pharmaceutically acceptable acid addition salts comprehended by the invention are useful as medicines because of their high anti-plasmin activity and their good stability in blood. Particularly useful are the substituted phenyl esters of t-AMCI-LA and PAMBA, the substituted phenyl portion of which is 4'-carboxyphenyl, 4'-carboxymethylphenyl, 4'-(2"-carboxyethyl)- phenyl, 4'-(2-carboxyvinyl)-phenyl, 4 (5" carboxyethoxy)-phenyl, 4-(5"-carboxy-n-pentyl)-phenyl, 4'-(1"- hydroxy- -carboxy-n-pentyDphenyl, 4-(1"-oxo "-carboxy-n-pentyl)-phenyl or 4'-(2"-amino-2"-carboxyethyl)- phenyl. Their pharmaceutically acceptable acid addition salts also are preferred.

Anti-plasmin activity of these new aryl esters is assayed by either of the fibrinolytic or caseinolytic method. In the caseinolytic method, the aryl esters of trans-AMCHA inhibit the plasmin activity several hundred times or several ten times more strongly than trans-AMCHA or benzyl trans-4-aminomethylcyclohexanecarboxylate, respectively, does.

Anti-fibrinolytic activities of these aryl esters of trans- AMCHA are several ten times more potent than those of trans-AMCHA or benzyl trans-4-aminomethylcyclohexanecarboxylate. The aryl esters of PAMBA, also possess high anti-fibrinolytic and anti-caseinolyltic activities which are several time more potent in the former and several ten to hundred times more potent in the latter than those of trans-AMCHA and PAMBA. Anti-plasmin activities of these esters of trans-AMCHA and PAMBA determined by the caseinolytic and fibrinolytic methods are listed in Table 1 in which the activities are represented in relative values on molar basis to each of the phenylesters of trans- AMCHA and PAMBA. Comparisons of various activities of these aryl esters with those of the previously known inhibitors, trans-AMCHA, PAMBA and benzyl trans- 4-aminomethylcyclohexanecarboxylate, are shown in Table 2.

As apparent from the data of Table 1 and Table 2, the new aryl esters of trans-AMCHA and PAMBA leap into several ten to hundred times more potent in their activities. Although the reason why the aryl esters of the invention can show markedly high pharmacological activities is not fully clear still yet, it is believed that the esters of the invention in which aromatic ring is directly linked to the carboxyl group of the t-AMCHA or PAMBA portion are more eifective in anti-plasmin activities than the known benzyl esters in which the aromatic ring is connected through a carbon chain with the carboxyl group.

The aryl esters of trans-AMCHA and PAMBA strongly inhibit the action of plasmin itself as Well as the activation of plasminogen to plasmin, whereas it has been reported that trans-AMCHA and PAMBA inhibit only the activation of plasminogen to plasmin (S. Okamoto and U. Okamoto, Keio J. Med. (Tokyo) 11, 105 (1962); A. I-I. C. Dubber et al., Brit. J. Haematol., 11, 237 (1965); M. Maki and F. K. Beller, Thrombos. Diathes. Haemorrh., 16, 668

(1965); and European J. Biochem, 6, 502 (1968)).

6 In addition to their superiority in inhibiting the plasmin Toxicities of these new esters generally are low both activity, these aryl esters of trans-AMCHA possess marked in oral and parenteral administration. For example, acute inhibitory actions on blood coagulation system including toxicities of some new esters are listed in the following thrombin, on trypsin and on kallikrein. These inhibitory table.

actions are not found or are very little in the previously 5 known antifibrinolytic agents, such as trans-AMCHA, u- Compounds testedanunocaproic acid, PAMBA and benzyl trans-4-ammo- NHZOHI @'COO AWI methylcyclohexanecarboxylate.

Compounds of the invention which possess inhibitory My}: Tommas' LDMmg/kg') actions on the fibrinolytic, blood clotting and kinin-form- 1O C6H5- 119.7 (Lv. mouse). ing systems may be useful for the treatment of various BI% %E i g g gy gffig hemorrhage (caused by defibrination) which will be ob- D-HOOCCH=CHCQHA- 1:06 (II ImOuSe): served in the primary hyperfibrinolysis and even in the g f f g- 6 g-X- secondary hyperfibrinolysis homeostatically following inmouse): travascular coagulation state. Anti-trypsin and anti-kalli- 15 1 5552 muse) 9180 krein activities of these compounds also support their clini- NOTE.-I.V.=Intra-venous administration; I.P.=Intra-peritonea1 adcal utility in the treatment of acute pancreatitis. m1I1iStwtiOH;P-O-=Per TABLE 1 Relative activities of esters of trans-AMCHA and PAMBA -Plasma Anti-plasmln Aryl Casein Fibrin Antithrombin Casein Fibrin Phenyl 10 100 100 100 o-Toluyl 44 32. 4 1. 67 45 m-Toluyl 100 108 45. 5 50. 2 p-Toluyl 173 165 71. 5 92. 1 3 ,4-dimethyl-phenyl 91 127 61 o-Methoxy-phenyl. 27.5 53 9 5.0 p-Methoxyl-phenyl 120 147 416 6 o-Metboxy-p-methylphenyl 96 5 o-Methoxy-p-iormylphenyl. 233 0 o-Chloro-phenyl 162 71. 5 43 1 m-Chloro-pheny 136 85 3 250 34 8 pChloro-phenyl. 250 157 250 178 o-p-Dichloro-phenyl- 14 200 2 159 o-Bromo-phen 97 172 55 5 141 -tert-Butyl-phenyL. 149 171 163 p-Hydroxy-phenyl-..-- 7 3 96. 5 94.4 p-Hydroxymethyl-phenyL. 172 169 250 85 6 p-Amino-phenyl 69 96. 5 156 94 p-Nitro-pbenyl 187 242 555 1, 900 o-Nitro-p-methoxy-carbonyl-phenyl- 49 323 p-Sulfamoyl-phenyl 428 424 p-Benzyloxycarbonyl-pheny 970 1, 490 p-Carboxy-phenyl 116 35. 2 14. 3 90. 5 77 p-Garboxy'methyl-phenyL- 100 80 89. 3 66. 7 53. 8 p-(2-carboxy-ethyl)- henyl. 126 56. 8 70 77 m-(2-carboxy-ethyD-pheny1-- 44 2 43.2 27.8 21 6 p-(2-carboxy-vinyl)- h nyl..- 198 226 8. 93 162 215 p-(2-earboxy-2ramino-ethy1)-pheny1- 86. 0 80. 2 23. 8 33. 1 28. 9 p-(2-carboxy-ethoxy)-phenyl 118 111 58. 7 61 p-(5-carboxy-pentyl)-pl1enyl 200 254 171 223 p-(l-hydroxy-fi-carboxy-penty 211 194 p-(1-oxo-5-carboxy-pentyl)-phenyl 290 212 3-pyridyl 200 Pyridine N-oxide-3-yL 33 148 a-Naphthyl 68 I 8. 8 fi-Naphthyl 87 3-carboxy-2naphtby 9 14. 8

TABLE 2.-CONCENTRATION OF DRUGS CAUSING 50% INHIBITION 1 Anti-plasnnn Caseinolysis 2 Fibrinolysis I Antl-thrombin l Anti-trypsin Anti-kallikrein fl trans-AMCHA 2, 400 (1) 59 (1) Inactive Inactive Inactive. PAMBA 4, 000 (0.6) 110 (0. 54) Inactive Very weak Do. Benzylester of trans-AMCHA. 56 (43) 37 (1. 6) 500 (1) 240 (1) Do. Phenylester of trans-AMOHA 2 (1, 200) 1. 8 (32. 8) 5 (100) 50 (4.8) Less than 1,000. Phcnylester of PAMBA 12 (200) 9 (6. 6)

1 The concentrations are represented as moleslmi.

I Antioaseinolytic activity of the compounds was determined by the method of M. Shimizu, et al. [Chem. Pharm. Bull. (Tokyo), 16, 357 (1968)]. 0.5 ml. of euglobulin solution prepared from human blood was preincubated with 1 m1. of 2% casein solution in phosphate bufier-saline (pH 7.4) and 0.4 ml. of the phosphate butter-saline containing various amounts of an inhibitor to be tested at 37 C. for 3 minutes. Then, 0.1 m1. of streptokinase solution (200 units) was added and the mixture was incubated at 37 C. for 20 minutes. After incubation, 2ml. of 17% perchloric acid was added, allowed to stand at room temperature for about 1 hour, and centrifuged. The extinction of the clear supernatant was measured at 280 my against an enzyme blank to which the streptokinase solution was added after the addition of perchlon'c acid. The inhibition rates were calculated by comparison with the control run which contained no inhibitor.

4 Antifibrinolytic activity was determined according to the method 0! S. Okamoto and U. Okamoto [Keio J. Med. (Tokyo), 11, 105 (1962)]. 0.1 ml. of the human euglobulin solution was mixed with 0.5 ml. of the phosphate bufiersaline containing various amounts of an inhibitor to be tested. 0.1 ml. of thrombin solution (5 units) and 0.1 m1. otstreptokinase solution (100 units), and finally 0.2 ml. of 0.5% bovine fibrinogen solution in phosphate bufler-saline was added to the above mixture. The lysis time of the fibrin clot formed was measured at 25 C. after the addition of fibroinogen. Inhibitory actions of the compounds are represented as the concentrations of the compounds for doubling the clot lysis time of the control run which contained no inhibitor.

4 .Anti-thrombin activity of the compounds was determined by the fibrin-clot forming reaction due to thrombin. Inhibitory actions of the compounds are represented as the concentrations of the compounds for doubling the clotting time of the control run which contained no inhibitor.

5 Anti-trypsin activity of the compounds were determined by the caseinolyt'ic reaction due to trypsin.

Anti-kallikrein activity of the compounds was determined by the kinin-iorming reaction due to human plasma kallikrein activated with acetone followed by kinin bioassay using isolated guinea pig uterus, or by the esterolytie reaction of aN-tosyl-lrarginimethylester due to plasma kallikrein.

Nora-Figures in the paretheses indicate relative activities.

Now the following examples will be given to show the present invention in detail.

EXAMPLE 1 8 hydrochloride in the form of prisms with a melting point of 255 C. (decomposed).

Elementary analysis for C H O NCl (M.W. 313.78) (percent): Calcd.: C, 57.41; H, 6.42; N, 4.46; CI, 11.30.

2.5 g. (0.011 mole) of 4-benzyloxycarbonylphenol and Found (Percent): 5728; 6-39; N4-613 1.2 g. of triethylamine were dissolved in ml. of dried tetrahydrofuran. To this solution was added 3.1 g. (0.010 mole) of trans-4-N-benzyloxycarbonylaminomethyl-cyclohexane-l-carboxylic acid chloride dissolved in 10 ml. of dried benzene. The mixture was stirred for about one EXAMPLES 2-10 By repeating the substantially same procedures as in Example 1, various new aryl esters were prepared. The

10 results are summarized in the following Table 3.

TABLE 3 NHzCHr QC o O-Aryl Elementary analysis (Found) Example Yield number Aryl Salt M.P. 0.) (percent) C H N 01 2 Cl H01 201 (dec.) 88 49.96 5.18 4.35 31.79

3 C1 HO]. 2102l3 (dec.)- 78.3 45.37 4.42 4.06 38.10

4 CH; HCl 241(dee.) 78 64.73 8.14 4.81

6 CH5 H01 256 (dee.) 86 66.48 8.63 4.86

7 HCl 212-214 (dec.)- 42 59.17 7.59 4.66

8. COOH H01 181-183 (dee.)- 52.69 5.81 3.98

OooH-i z zO 9 2-HC1 262 (dec.) 75 52.50 6.88 8.97

10 OCH: HCl 188-191 (dec.)- 46 60.44 7.57 4.79

hour at room temperature, heated to -80 C. for 30 EXAMPLE 11 minutes and then evaporated to dryness in vacuo. The residue was dissolved in ethyl acetate, washed several times with water, dried and evaporated to obtain colorless syrup. After cooling, the syrup changed to solid, which was recrystallized from ethanol to obtain 4.9 g. (88%) of 4'-benzyloxycarbonylphenyl trans-4-H-benzyloxycarbonylaminomethylcyclohexane-l-carboxylate with a melting point of 98 -100 C.

2.5 g. (0.005 mole) of this ester was dissolved in 10 ml. of tetrahydrofuran and 20 ml. of methanol. To this solution were added 2 ml. of 25% methanolic hydrochloric acid and 0.5 g. of palladium on carbon. The mixture was treated with hydrogen stream under an atmospheric pressure at room temperature. After the absorption of the theoretical amount of hydrogen, the catalyst was filtered off and the filtrate was evaporated in vacuo at low tem perature to obtain white crystals. Recrystallization of the crystals from ethanol yields 1.0 g. of 4'-carboxyphenyl trans 4 aminomethylcyclohexane l-carboxylate 2-Nitro-4-methoxycarbonylphenyl trans 4 N-benzyloxycarbonylaminomethylcyclohexane 1 carboxylate was prepared by reacting methyl 3nitro-4-hydroxybenzoate with trans 4 N-benzyloxycarbonylaminomethylcyclohexane-l-oarboxylic acid chloride according to the process of Example 1.

2.4 g. of this ester was dissolved in 10 ml. of 20% hydrobromic acid solution in acetic acid. The mixture was warmed to about 50 C. for 10 minutes, cooled and added with diethyl ether to eifect precipitation. The crystals obtained were washed well with diethyl ether and recrystallized from ethanol-diethyl ether to obtain 1.2 g. (56%) of 2 nitro 4' methoxycarbonylphenyl trans-4-aminomethylcyclohexane 1 carboxylate hydrobromide in the form of prisms with a melting point of 183 l86 C.

Elementary analysis for C H O N Br (M.W. 417.26) (percent): Ca1cd.: C, 46.05; H, 5.07; N, 6.71. Found (percent): C, 46.24; H, 4.94; N, 6.57.

EXAMPLES 12-16 the form of white crystalline powder with a melting point of 252254 C. (dec.).

By repeating the substantially same procedures as in Elementary analysis for C1 1H22O NBl (M.W. 384.27) Example 11, various new aryl esters were prepared. The (percent): Calcd. C, 53.16; H, 5.77; N, 3.64; Br. 20.80. results are summarized in the following Table 4. 5 Found (percent): C, 53.07; H, 6.29; N, 3.71; Br, 20.84.

TABLE 4 NH.cH.-@ooo-Ar 1 Elemeat sgrglganalysis Example Yield number Aryl Salt M.P. C.) (percent) 0 H N Br 12 HBr 190-192 (dec.). 85 46.82 5.57 7.67

1a OOH; HBr 242 245 (dec.)- 75 52.02 6.28 3.66

- CHO 14 HBr 261 (dec.) 86 42.53 5.43 7.23 20.67

BO2NH| 15- 2-HBr 193-195 (dec.)- 52.2 39.27 5.01 7.44 39.93

HBr 278 (dee.) 58 46.93 5.79 8.54

EXAMPLE 17 EXAMPLES 18-19 2.0 g. of benzyl 4-hydroxycinnamate and 1.0 g. of tri- 35 By repeating the substantially same procedures as in ethylamine were dissolved in 10 ml. of dried dioxane. To Example 17, various new aryl esters were prepared. The

this solution was added 2.5 g. of trans-4-N-benzyloxyresults are summarized in the following Table 5.

TABLE 5 Elementary analysis (Found) Example M.P. Yield number Aryl Salt 0.) (percent) 0 H N Br 18 HBr 210 (dec.)- 60 51.98 5.94 4.16 20.69

CHzCOOH 19 HB: 195 (dec.). 65 55.60 6.75 3.42

(CHahCOOH carbonylaminomethylcyclohexane-l-carboxylic acid chlo- EXAMPLE 20 ride in 10 ml. of dried benzene. The mixture was stirred for about one hour at room temperature and then heated to 60-80 C. for minutes. After cooling, crystallized triethylamine hydrochloride was removed by filtration, and the filtrate was evaporated to obtain colorless syrup which was changed to solid. The crude product was recrystallized from ethyl acetate and petroleum ether to obtain 3.2 g. (75%) of 4'-(2"-benzyloxycarbonylviny1) phenyl trans 4 N-benzyloxycarbonylaminomethylcyclo- 4' N (2" benzyloxycarbonylamino 2" benzyloxycarbonylethyl)phenyl trans 4 N benzyloxycarbonylaminoethylcyclohexane 1 carboxylate with a melting point of 137139 C. was obtained by reacting benzyl N benzyloxycarbonyltyrosinate with trans 4 N- benzyloxycarbonylaminomethylcyclohexane 1 carboxylic acid chloride in the same manner as in Example 17. 4.5 g. of the obtained ester was dissolved in 30 ml.

of glacial acetic acid, and to the resulting solution 0.5 22 3?; zgifi gg i g gf i .32 2"? crystanme g. of 10% palladium on carbon was added. The mixture E16 meat ary analysis for C H 06H W 527 62) was treated with hydrogen stream under an atmospheric (percent): Ca1cd C 72 82 if 22 a ('perceht): pressure at room temperature. After the absorption of C, 72.23; H, 615. 65 31;: thieorgtrclzgtl arclligunt 5&2; lilyclirogrifi, the catalyst wtas ere o y a mg 0 y me one am in ace 1c gii g g sg gg gg i g fifi zgg zigggg acid, diethyl ether and petroleum ether to the filtrate, f crude product was precipitated and then collected by or about 20 minutes at room temperature. Then the fil t mixture was cooled enough and then added with 50 ml. tra Ion The crude product was recrystalhzed from ethanol-ether to obtan 2.2 85.47 t 4' 2" of dried diethyl ether. The crude product precipitated boxy 2 amino ethlyl) i 3 ig fifi.

Was colleflted y filtration, Wahed with diethyl ether and cyclohexane 1 carboxylate dihydrochloride in the form recrystallized from ethanol-diethyl ether to obtain 1.4 of powder with a melting point of 215 C. (dec.).

g. (62%) of 4' (2"-carboxyvinyl)phenyl trans-4-amino- Elementary analysis for C H O N -2HCl (M.W. methylcyclohexane 1 carboxylate hydrobromide in 393.31) (percent): Calcd. C, 51.91; H, 6.66; N, 7.12;

11 Cl, 18.03. Found (percent): C, 51.90; H, 6.56; N, 7.22; C1, 18.32.

EXAMPLES 21-30 By repeating the substantially same procedures as in Example 20, various new aryl esters were prepared. The results are summarized in the following Table 6.

TABLE 8 Elementary analysis Y1 10 (Found) E l e nli i h r Aryl Salt M.P. 0.) (percent) 0 H N 21 IIIHz 211131 205-207 (dec.).. 02.4 41.13 5.52 5.75 15152.70

@omcnooon 22 NH: 2CHaSO1H 204-206(dee.) 43.33 0.54 5.55 811.87

--0H40H0ooH-H,o

2s H01 236-238(dee.)-- as 59.89 0.01 4.08

Gomcmooon 24---;...-.-.--.: CH1SO7H 210-215 90 55.07 0.04 5.52 sa.o9

Qomcmooon 25 CHzCHzCOOH H01 107-100 81.3 50.77 0.98 4.17 0110.70

20 H01 213(dee.).......- 34.3 57.03 0.70 4.20 0110.55

@OCHzCHzCOOH Q-cowmmoon -NHCH1C00H 29 fi H01 2002100155.. 20 02.25 0.05 4.00 0110.00

coon N 30 H01 216-218(dec.)-. 52.50 0.03 8.45 0110.24

EXAMPLE 31 ing with ice water and the mixture was stirred for one 3.2 g. of 4'-(2"-benzyloxycarbonylvinyl)phenyl trans-4- N-benzyloxycarbonylaminomethylcyclohexane-1 canboxylate (preparated in Example 17) was treated in the same manner as in Example 20 to obtain 1.8 g. (87%) of 4-2"- carboxyethyl)phenyl trans-4-aminomethylcyclohexane-lcarboxylate hydrochloride in the form of white crystalline powder with a melting point of 236-238 C. (dec.).

EXAMPLE 32 12.4 g. (0.04 mole) of trans-4-aminomethylcyclohexane-l-carboxylic acid chloride was dissolved in m1. of benzene. The resulting solution was added dropwise to a solution of 5.4 g. (0.044 mole) of 4-hydroxybenzaldehyde and 6.4 g. (0.08 mole) of pyridine in 20 ml. of dioxane at room temperature, and allowed to stand overnight. After the removal of pyridine hydrochloride by filtration, the filtrate was evaporated to dryness in vacuo. To the residue water and benzene were added, and then the benzene layer was washed enough with water, dried and evaporated to dryness in vacuo to obtain colorless crystals. Recrystallization of the crystals from ethanol-petroleum ether yielded 10 g. (62.5%) of 4'-formylphenyl trans-4-N-benzyloxycarbonylaminomethylcyclohexane 1 carboxylate in the form of powder with a melting point of 105 107 C.

hour. When the mixture was poured into cold water, white crystals were precipitated. The crude crystals were washed with water, dried and recrystallized from ethanol and further from ethanol-petroleum ether to obtain 6.3 g. (64%) of 4'-hydroxymethylphenyl trans-4-N-benzyloxycarbonylaminomethylcyclohexane-l-carboxylate in the form of needles with a melting point of 112ll3 C.

Elementary analysis for C H O N (M.W. 397.45) (percent): Calcd. C, 69.50; H, 6.85; N, 3.52. Found (percent): C, 69.37; H, 6.90; N, 3.62.

6.3 g. (0.016 mole) of the ester was dissolved in ml. of methanol. To the resulting solution were added 2 g. of 30% methanolic hydrochloric acid and 3 g. of palladium on carbon. The mixture was treated with hydrogen stream under an atmospheric pressure at room temperature. After the absorption of the theoretical amount of hydrogen the catalyst was filtered off and the filtrate was evaporated to dryness in vacuo. The white residue was recrystallized from methanol-diethyl ether to obtain 2.5 g. (52%) of 4'-hydroxymethylphenyl trans-4-aminomethylcyclohexane 1 carboxylate hydrochloride in the form of white needles with a melting point of 241-242 C. (dec.).

13- Elementary analysis for C H O NCl (M.W. 299.81) (percent): Calcd. C, 60.09, H, 7.39; N, 4.67; Cl, 11.82. Found (percent): C, 60.21, H, 7.48; N, 4.70; Cl, 11.78.

EXAMPLE 33 4-(1-oxo 5" benzyloxycarbonyl-n-pentyl)phenyl trans 4 N-benzyloxycarbonylaminomethylcyclohexanel-carboxylate with a melting point of 72-75 C. was prepared by reacting 4-(1'-oxo-5'-benzyloxycarbonyl-n-pentyl)phenol With trans-4-N-benzyloxycarbonylaminomethylcyclohexane-l-carboxylic acid chloride. Yield 86.5%.

Elementary analysis for C H O N (M.W. 585.67) (percent): Calcd. C, 71.77; H, 6.71; N, 2.39. Found (percent): C, 71.19; H, 6.53; N, 2.76.

The ester was treated with sodium borohydride in the same manner as in Example 32 and the resulting product was recrystallized from isopropyl ether to obtain 4'-(1"- hydroxy-S" benzyloxycarbonyl-n-pentyl)phenyl trans-4- N-benzyloxycarbonylaminomethylcyclohexane 1 carboxylate with a melting point of 62-65 C. Yield 79%.

Elementary analysis for C35H41N07 (M.W. 587.69): (percent): Calcd. C, 71.53; H, 7.03; N, 2.38. Found (percent): C, 71.49; H, 7.03; N, 2.81.

The above-resulted compound was treated in the same manner as in Example 20 to obtain 4-(1"-hydroxy-5- carboxy-n-pentyl)phenyl trans 4-aminomethylcyclohexane-l-carboxylate hydrochloride in the form of prisms with a melting point of 150l54 C. Yield 53%.

Elementary analysis for C H O NCl (M.W. 399.91): (percent): Calcd. C, 60.06; H, 7.56; N, 3.50; CI, 8.87. Found (percent): C, 60.15; H, 7.56; N, 3.76; Cl, 9.37.

EXAMPLE 34 4'-(1" hydroxy 5" benzyloxycarbony]-n-pentyl) phenyl trans 4 N-benzyloxycarbonylaminomethylcyclohexane-l-carboxylate obtained in Example 33 was treated with hydrobromic acid-acetic acid in the same manner as in Example 1 to obtain 4-(l"-bromo-5"-carboxy-n-pentyl) phenyl trans 4 aminomethylcyclohexane-l-carboxylwas dissolved in 40 ml. of dried benzene. To the resulting mixture were added 1.5 g. of triethylamine and 2.6 g. (0.01 mole) of benzyl 4-hyclroxycinnamate dissolved in ml. of dried benzene. The solution was heated to 70 -80 C. for minutes on a water bath. After cooling the benzene layer was washed enough with water, dried and evaporated to dryness. The residue was recrystallized from ethyl acetate-petroleum ether to obtain 3.1 g. (63.0%) of 4'-(2'- benzyloxycarbonylvinyl)phenyl trans 4-N-tert-butyloxycarbonylaminomethylcyclohexane 1 carboxylate in the form of small needles with a melting point of 141- 142 C.

Elementary analysis for CC H O N (M.W. 493.58) (percent): Calcd. C, 70.56; H, 7.15; N, 2.84. Found (percent): C, 70.22; H, 6.59; N, 2.99.

The thus obtained compound was treated in the same manner as in Example 17 to obtain 4'-(2"-carboxyvinyl)- phenyl trans-4-aminomethylcyclohexane-l-carboxylate hydrobromide in the form of white crystalline powder with a melting point of 252-254 C. (dec.). Yield 68%.

EXAMPLE 36 To 4.2 g. of trans-'4-aminomethylcyclohexane-l-carboxylic acid chloride hydrochloride was added 2.2 g. of phenol dissolved in ml. of dried tetrahydrofuran. The mixture was refluxed for about 30 minutes and evaporated to obtain white crystalline residue. Recrystallization of the residue from ethanol-diethyl ether yielded 4.0 g. (75%) of phenyl trans-l-aminomethylcyclohexane-l-carboxylate hydrochloride in the form of needles with a melting point of 213-215 C. (dec.).

Elementary analysis for C H O NCI (M.W. 269.77) (percent): Calcd. C, 62.33; H, 7.47; N, 5.19. Found (percent): C, 62.37; H, 7.56; N, 5.37.

EXAMPLES 37 40 By repeating the substantially same procedures as in Example 36, various new aryl esters were prepared. The results are summarized in the following Table 7.

TABLE 7 NHzCH2-@-COO-Aryl Elementary analysis (Found) Example Yield 0. Aryl Salt M.P. 0.) (percent) 0 H N 01 37 01 HO] 198-202 (dec.)-. 80 56.21 6.42 23.1

38 HCl 200-203 (dec.)-. 75 65.66 6. 96 4. 51

39 HCl 239 (dec.) 62 66.67 6.92 4.42

40 H01 243 (dec.) 69.15 7.03 4.53

ate hydrobromide in the form of powder with a melting EXAMPLE 41 pomt of 139 Yleld 394% 65 To 3.0 g. of trans-4-aminomethylcyclohexane-l-car- Elementary analysis for C H O NBr (M.W. 507.27) (percent): Calcd. C, 47.35; H, 5.76; N, 2.76; Br. 31.51. Found (percent): C, 47.31; H, 5.90; N, 3.02; Br, 30.92.

EXAMPLE 35 Trans 4 N-tert butyloxycarbonylaminomethylcyclohexane-l-carboxylic acid chloride in the form of syrup prepared by reacting 2.3 g. of trans-4-N-tert-butyloxycarbonylaminomethylcyclohexane 1 carboxylic acid with boxylic acid chloride hydrochloride, 10 ml. of o-cresol was added to occur exothermic reaction. The resulting mixture was allowed to stand for about 30 minutes at room temperature and the crystals were precipitated with a large amount of diethyl ether. The crystals were washed enough with diethyl ether to remove cresol, and recrystallized from methanol-diethyl ether to obtain 3.2 g. (81%) of Z-methylphenyl trans-4-aminomethylcyelohexane-l-carboxylate hydrochloride in the form of white leaflets with 2.4 g. of thionyl chloride in the presence of triethylamine a melting point of 181-l83 C.

15 Elementary analysis for C H NCl (M.W. 283.79) (percent): Calcd. C, 63.48; H, 7.81; N, 4.94. Found (percent): C, 63.36; H, 7.71; N, 5.23.

EXAMPLES 42-49 By repeating the substantially same procedure as in Example 41, various new aryl esters were prepared. The results are summarized in the following Table 8.

TABLE 8 macro-@w 0 O'Aryl Elementary analysis (Found) Example Yield No. Aryl Salt M.P. 0.) (percent) 0 H N 01 42 OCH; H01 212-213 77 60.43 7.36 4.78

43...::::::= HCI 215-217 (dec.). 83 60.48 7.39 11.51 3::

46...::::::::: Cl HCl 175-177..--..':;: 85 55. 40 6.11 23. 32

47.-.'. Cl HCI 191194 (160.). 80 55.47 6.34 23. 52

48....:.-.:::::.:: B! HCl 169-171.::::: 83 47.81 5. 38 4. 36 .15:

49-..::::: CHa HCl 215 (dec.)....:: 85 64. 64 8. 08 5. 02 3.-.:

EXAMPLE 5O EXAMPLE 51 To 2.1 g. of trans 4-aminomethylcyclohexane-l-carbonyl chloride was added g. of benzyl 4-hydroxyphenylpropionate with stirring. The resulting mixture was heated to 6070 C. with stirring for about min. Vigorous reaction occurred with evolution of gaseous hydrochloride to give a homogeneous syrup. After cooling, white crystalline powder was precipitated by adding 100 ml. of dry diethylether and mixing enough. The crystals were collected by filtration and washed enough with dry diethylether. Then the crystals were dissolved in methanol and precipitated by adding diethyl ether to obtain 3.74 g. (85%) of 4'-(2"-benzyloxycarbonylethyl)phenyl trans-4- arnino-methylcyclohexane-l-carboxylate hydrochloride in the form of white prisms with a melting point of 171- 192 C.

Elementary analysis for C H O N (M.W. 439.95): (percent): Calcd. C, 66.73; H, 7.00; N, 3.24; CI, 8.21. Found (percent): C, 66.97; H, 6.85; N, 3.45; Cl, 8.39.

The prisms obtained were dissolved in the mixture of 20 ml. of glacial acetic acid and 20 ml. of dry dimethylformamide. Then the resulting mixture was treated with hydrogen stream under an atmospheric pressure at room temperature in the presence of 0.5 g. of 10% palladium on carbon. After absorption of the theoretical amount of hydrogen, the catalyst was filtered off, and to the filtrate 16.6 g. (0.1 mole) of 4-hydroxyphenylpropionic acid and 15.8 g. of pyridine (0.2 mole) were dissolved in ml. of dry dioxane. To the mixture, trans-4-N-benzyloxycarbonylaminomethylcyclohexane-l-carbonyl chloride dissolved in 150 ml. of dry benzene was added, and the resulting mixture was stirred for 30 hours at room temperature. Then the precipitated crystals were filtered 011 and the filtrate was allowed to stand overnight and the crystals separated were filtered ofl again. To the filtrate 100 ml. of diethyl ether was added and allowed to stand overnight. The white crystals were collected by filtration and recrystallized from ethyl acetate-petroleum ether to obtain 6 g. (13.6%) of 4-(2"-carboxyethyl)phenyl trans-4-N- benzyloxycarbylaminomethylcyclohexane l-carboxylate with a melting point of 108 C.

Elementary analysis for C H O N (M.W. 439.49): (percent): Calcd. C, 68.32; H, 6.65; N, 3.19. Found (percent): C, 68.60; H, 6.42; N, 2.94.

2.1 g. (0.005 mole) of the crystals was dissolved in 500 ml. of glacial acetic acid, and to the resulting mixture, 1.0 g. of 10% palladium on carbon was added. Then the solution was treated with hydrogen stream under an atmospheric pressure at room temperature. After absorption of the theoretical amount of hydrogen, the catalyst was filtered off and to the filtrate a small excess amount of hydrochloric acid-acetic acid was added and further dry ether was added. The white crystals were collected by filtration and recrystallized from ethanol-diethyl ether to obtain 1.28 g. (82%) of 4' (2"-carboxyethyl)phenyl trans-4-aminomethylcyclohexane-1-carboxylate-hydrochloride in the form of white crystals with a melting point of 236-238 C. (dec.).

EXAMPLE 5 2 19 g. (0.1 mole) of sodium 4-hydroxyphenylpropionate was suspended in 120 ml. of dry dioxane. To the mixture was added 31 g. (0.1 mole) of trans-4-N-benzyloxycarbonylaminomethylcyclohexane-l-carboxylate dissolved in 150 ml. of dry benzene and the resulting mixture was EXAMPLES 54-5 5 By repeating the substantially same procedures as in Example 53, various new aryl esters were prepared. The

stirred for 12 hours at room temperature. Then the pre- 15 results are summarized in the following Table 9.

TABLE 9 rrmom-Q-ooo-mr Elementary analysis (Found) Example M.P. Yield number Aryl Salt 0.) (percent) 0 H N 54 CH; HB! 231 (dec.). 83 57. 47 5.60 4.41

55 C1 HBr 235 (dec.)- 64 cipitation was filtered oif and the filtrate was evaporated. EXAMPLE 56 To the resulting solution 100 ml. of diethyl ether was added and the mixture was allowed to stand overnight. The crystals were collected by filtration and recrystallized from ethyl acetate-petroleum ether to otbain 4 g. (9.1%) of 4 (2-carboxyethyl)phenyl trans-4-N-benzyloxycarbonylaminomethylcyclohexane-l-carboxylate in the form of white crystals with a melting point of 102-105 C.

The ester was treated in the same manner as in Example 51 to obtain 4 (2 carboxyethyl)phenyl trans-4- aminomethylcyclohexane:l-carboxylate hydrochloride.

EXAMPLE 5 3 1.5 g. (0.011 mole) of 4-nitrophenol and 1.2 g. (0.012 mole) of triethylamine were dissolved in 20 ml. of dried tetrahydrofuran. To the resulting mixture was added 3.0 g. (0.01 mole) of 4 N-benzyloxycarbonylaminomethylbenzoic acid chloride dissolved in 20 ml. of dried benzene. The mixture was heated to 60-80 C. for one hour with stirring and evaporated in vacuo. The residue was dissolved in ethyl acetate and the mixture was washed several times with water and evaporated to obtain colorless syrup. After cooling the syrup changed to solid, which was recrystallized from ethanol to obtain- 3.1 g. (76%) of 4- nitrophenyl 4N-benzyloxycarbonylaminomethylbenzoate in the form of yellow needles with a melting point of 143145 C.

Elementary analysis for C H O N (M.W. 406.39): (percent): Calcd. C, 65.02; H, 4.46; N, 6.89. Found (percent): C, 65.27; H, 4.52; N, 6.73.

2.0 g. (0.005 mole) of this ester was dissolved in 10 3.2 g. of 4'-methoxyphenyl 4-benzyloxycarbonylaminomethylbenzoate in the form of white crystals with a melting point of -127 C. was prepared by reacting 1.4 g. (0.011 mole) of 4-methylphenol with 4-benzyloxycarbonylaminomethylbenzoic acid chloride. Yield 82%.

Elementary analysis for C H O N (M.W. 391.41) (percent): Calcd. C, 70.57; H, 5.41; N, 3.58. Found (percent): C, 70.82; H, 5.49; N, 3.41.

2.0 g. (0.005 mole) of this ester was dissolved in 10 ml. of tetrahydrofuran and 20 ml. of methanol. To the resulting solution were added 2 ml. of 25% methanolic hydrochloric acid and 0.5 g. of 5% palladium on carbon. Then the mixture was treated with hydrogen stream at room temperature under an atmospheric pressure. After the absorption of the theoretical amount of hydrogen, the catalyst was filtered off and the filtrate was evaporated to dryness in vacuo at low temperature. Recrystallization of the white crystals obtained above from ethanol-diethyl ether yielded 1.2 g. (82%) of 4'-methoxyphenyl 4-aminomethylbenzoate hydrochloride in the fom of white needles with a melting point of 263 C. (dec.).

Elementary analysis of C H O NCl (M.W. 293.74) (percent): Calcd. C, 61.32; H, 5.49; N, 4.76. Found (percent): C, 61.94; H, 5.25; N, 4.88.

EXAMPLES 57-64 By repeating the substantially same procedures as in Example 56, various new aryl esters were prepared. The results are summarized in the following Table 10.

TABLE NHgGHz-Q-OOO-Aryl Elementary analysis (Found) E N3. Aryl Salt M.P. 0.) percent) 0 H N 57....: CH; HCl 220((1B0.)..-.;: 84 65.85 6.08 4.88

58-": I H01 244 (dec.)---.;: 64 68.76 5.29 4.48

59.--: CH; H01 246 ((180).-..5 75 67.63 6.89 5.01

60...: OCH; H01 176-179....':.:;:: 80 G0. 89 5. 69

81...:: C1 H01 212-215 "T. 56. 61 4. 51

62...:; Cl H01 250252 (dec. 56.92 4.35

63...:2 Br 1101 228231(dee.).."r::::.;::: 49. 3.82 4.29

64..... OH: HC] 230 ((180.) -...'r 60 65. 60 5.98 5. M

EXAMPLE 65 hydrochloride was filtered off, and the filtrate was washed EXAMPLE 66 4.1 g. (0.01 mole) of benzyl N-benzyloxycarbonyltyrosinate and 1.2 g. of triethylamine were dissolved in 20 ml. of dried benzene. To the resulting solution was added 3.0 g. (0.01 mole) of 4-N-benzyloxycarbonylaminomethylbenzoic acid chloride dissolved in 20 ml. of dried benzene. The mixture was stirred for 30 minutes at room temperature and heated at reflux on a water bath for one hour. After cooling the separated triethylamine with water, dried and evaporated to obtain a white residue. Recrystallization from ethyl acetate-isopropyl ether yielded 6.0 g. of 4-(2"-benzy1oxycarbonylamino- 2-benzyloxycarbonylethyl)phenyl 4 N benzyloxycar- 'bonylaminomethylbenzoate with a melting point of 153 C.

Elementary analysis for C H O N (M.W. 672.70) (percent): Calcd. C, 71.41, H, 5.39; N, 4.16. Found (percent): C, 71.83; H, 5.32, N, 4.14.

3.4 g. (0.005 mole) of the ester was dissolved in 30 ml. of glacial acetic acid. To the resulting solution 0.5 g. of palladium on carbon was added. The mixture was treated with hydrogen stream at room temperature under an atmospheric pressure. After absorption of the theoretical amount of hydrogen, the catalyst was filtered 01?. To the filtrate 5 g. of 5% hydrochloric acid-acetic acid was added. The crude product was precipitated with diethyl ether and petroleum ether, collected and recrystallized from methanol-diethyl ether to obtain 1.2 g. (60%) of 4'-(2"-carboxy-2"-amino-ethyl)-phenyl 4-amin0methylbenzoate dihydrochloride in the form of needles with a melting point of 276 -279 C. (dec.).

Elementary analysis for C H N Cl (M.W. 387.28) (percent): Calcd. C, 52.72; H, 5.21; N, 7.23; CI, 18.31. Found (percent): C, 52.80; H, 5.24; N, 6.64; Cl, 17.90.

21 EXAMPLES 67-72 By repeating the substantially same procedures as in Example 66, various new aryl esters were prepared. The

4-N-benzyloxycarbonylaminomethylbenzoate with a melting point of 108 C.

The ester was reduced with sodium borohydride to obtain 4'-hydroxyrnethylphenyl 4-benzyloxycarbonylamiresults are summarized in the following Table 11. 5 nomethylbenzoate with a melting point of 130-132 C.

TABLE 11 NHz-Q-COO-Atfl Elementary analysis (found) Example Yield number Aryl Salt MP. 0.) (percent) H N 01 57.. B101 277279(dec.) 01 50.22 4.50 4.77

68......" E01 250252 (dec.).. 81 59.68 50.4 4.40

09----.-.- H01 245247(dec.) 83 01.00 5.39 4.22

- CHzCHzOOOH 70.------. onzomooon HGl 234-2a0(dec.).. 79 50.30 5.16 4.52 10.52

71..... 1101 277-279 (dec.).. 85 54.75 5.20 3.82

H01 240-242 (dec.).. 74.5 58.00 5.08 4.18 10.49

72. moomcnzo OOH EXAMPLE 73 3.4 g. of 4-(2"-benzyloxycarbonylvinyl)phenyl 4-benzyloxycarbonylaminomethylbenzoate in the form of small needles with a melting point of 145 -147 C. was prepared by reacting 2.5 g. (0.01 mole) of benzyl 4-hydroxycinnamate with benzyloxycarbonylaminomethylbenzoic acid chloride. Yield 65%.

Elementary analysis for C H O N (M.W. 521.54) (percent): Calcd. C, 73.69; H, 5.22; N, 2.68. Found (percent): C, 74.25; H, 5.30; N, 2.85.

2.5 g. (0.005 mole) of the thus obtained ester was treated with hydrobromic acid-acetic acid in the same manner as in Example 5 3 and the resulting product was recrystallized from methanol-diethyl ether to obtain 1.6 g. (83%) of 4'-(2-carboxyvinyl)phenyl 4-aminomethylbenzoate hydrobromide in the form of prisms with a melting point of 273 C. (dec.).

Elementary analysis for C H O NBr- /2H 0 (M.W. 387.23): Calcd. (percent): C, 52.73; H, 4.43; N, 3.62. Found (percent): C, 52.58; H, 4.78; N, 3.61.

oxycarbonylaminomethylbenzoic acid chloride in the same manner as in Example 32 to Obtain 4'-formylphenyl Then the above-resulted compound was treated with hydrogen stream in the presence of palladium on carbon in the same manner as in Example 32 to obtain 4-hydroxymethylphenyl 4-aminomethylbenzoate hydrochloride in the form of prisms. M.P. 295 C.

Elementary analysis for C H O NCI (M.W. 293.76) Calcd. (percent): C, 61.33; H, 5.49; N, 4.76. Found (percent): C, 61.62; H, 5.27; N, 4.58.

EXAMPLE To 4.2 g. of 4-aminomethylbenzoic acid chloride hydrochloride, 15 ml. of fused phenol was added. The mixture was heated for one hour on a water bath. Then crystals were precipitated by adding diethyl ether and collected from the mixture. Then crude product was washed enough with diethyl ether to remove phenol and recrystallized from methanol-diethyl ether to obtain 4.5 g. (86%) of phenyl 4-aminomethylbenzoate hydrochloride in the form of white powder with a melting point of 248 C. (dec.).

Elementary analysis for C H O NCl (M.W. 263.72): Calcd. (percent): C, 63.75; H, 5.35; N, 5.31. Found (percent): C, 63.99; H, 5.44; N, 5.39.

EXAMPLES 76-80 By repeating the substantially same procedure as in Example 75, various new aryl esters were prepared. The results are summarized in the following Table 12.

TABLE 12 NHzCHz-QCOO-Aryl Elementary analysis (Found) Example M.P. Yield number Aryl Salt 0.) (percent) 0 H N 76 HCl 240 (dec.) 64.72 6.77 5.53

77 Gel H01 255 ((180.) 79 56.89 4.47 4. 67

78 CH: H01 203-205 78 62.99 6.12 5.10

79 CH; H01 220 (dec.) 65.88 6.08 4.92

80 OCH; H01 176479 61.01 5.50

The following Examples A to D show the detailed synthetic procedures for the preparation of some starting compounds usable in the present invention, which are new and have not been disclosed.

EXAMPLE A-TRANS 4 N-BENZYLOXYCARBON- YL-AMCHA CHLORIDE To 6.3 g. of trans-AMCHA dissolved in 16 ml. of 10% aqueous sodium hydroxide solution, 8.2 g. of benzyloxycarbonyl chloride and 20 ml. of 10% aqueous sodium hydroxide solution were added over 15 min., with cooling with ice water and vigorous stirring. Stirring was contin ued for 1 hr.

The white crystals precipitated were dissolved by adding water and acidified with hydrochloric acid solution with cooling. The white precipitate as formed was collected, washed with water, dried and recrystallized from benzenepetroleumether to have 10.7 g. of trans-4-N-benzyloxycarbonyl-AMCHA as needles. M.P. 115 117 0., yield 92%.

Elementary analysis for C H O N (M.W. 291.34) (percent): Calcd. C, 65.96; H, 7.26; N, 4.81. Found (percent): C, 66.34; H, 7.33; N, 5.07.

The thus obtained trans 4 N benzyloxycarbonyl- AMCHA (5.0 g.) was mixed with 5 ml. of thionyl chloride and warmed to 40 C. for 30 min. Vigorous reaction took place and a homogenous solution was formed. After cooling, 50 ml. of dried petroleum ether was added to the solution to precipitate white crystals, which were collected, washed with dried petroleum ether and dried in vacuo to give 1.4 g. of trans-4-N-benzyloxycarbonyl-AMCHA chloride as hygroscopic white crystals melting at 77- 82 C. (Yield 82%).

Elementary analysis for C H O NCl (M.W. 309.79) (percent): Calcd. C, 62.03; H, 6.51; N, 4.52; CI, 11.45. Found (percent): C, 62.42; H, 6.74; N, 4.37; Cl, 11.23.

solved in ml. of dried benzene, and to the solution, purified thionyl chloride (2.4 g.) was gradually added to have an exothermic reaction with precipitation. The reaction mixture was warmed at C. for 10 min. and then cooled. The precipitate was filtered off, and the filtrate and the washings were combined and concentrated to dryness under reduced pressure to give trans-4-N-terfbutyloxycarbonyl-AMCHA chloride as a syrup.

EXAMPLE CTRANS-AMCHA CHLORIDE 5.0 g. of trans-AMCHA was dissolved in 20 ml. of thionyl chloride. Gradually, crystals were precipitated. After 30 min., ether was added to the reaction mixture and the crystals were collected and dried in vacuo to give 5.4 g. of trans-AMCHA chloride hydrochloride as highly hygroscopic white needles.

EXAMPLE D4-HYDROXYARYL DERIVATIVES -To a solution of 3.0 g. of 4-hydroxyphenylacetic acid in 20 ml. of 4% aqueous sodium hydroxide and 30 ml. of ethanol, 3.0 g. of benzylchloride was added and the resulting mixture was heated at reflux on an oil bath at 120 C. for 1.5 hrs. After completion of the reaction, ethanol was removed to give a syrup which changed to solid on cooling. The resulting solid was treated with 20 ml. of ether. The separated water layer was removed, and the ether layer was washed with 5% aqueous sodium carbonate solution, dried and evaporated. The resulting white residue was recrystallized from petroleum ether to give 2.3 g. of benzyl 4-hydroxyphenylacetate as white prisms melting at 8892 C. (Yield 46.5%.)

Elementary analysis for C H O (M.W. 242.26) (percent): Calcd. C, 74.36; H, 5.83. Found (percent): C, 74.51; H, 5.94.

In the same manner as above, the following new 4- hydroxyaryl derivatives were synthesized.

Elementary anal. (found, percent) Yield p-Hydroxyaryl derivatives M.P. (B.P.) C H N (percent) p-HO-(CuHr)-CH=CHCO 0B2. 89- 75. 8 5. 6 37 D-HO(C5H4)CH2CH3COOBZ 199/1 mm. Hg 75.1 6.3 35 p-HO-(OrHD-CO (CH2)4COOBZ 90- 73. 0 6. 7 32 p-H0(CH4)-(CH) -COOBz (213.5/1 mm. Hg) 40-41 76.4 7.3 37 p-HO--(OHr)CH-CH(NHCbz)COOBz 116-118 70.3 5.7 30 p-HO(CaH4)O(CHz)zCOOBZ (200-201/1 mm. Hg) 74-78. 70. 4 6. 1 25. 5 m-HO(CaH4)CH CH COOBz (194-196/1 mm. Hg) 75.2 6.3 28.5 2,4-dibenzyloxyearbouyl ph rmnl 81-83 73. 2 5. 1 29 3-ber1zyloxycarbonyl-fl-napthnl 86-87 76. 1 5. 3 37 6-benzyloxycarbouyl-3-pyridinol-hyd10chloride.. 142-145 (dee.) 58.4 4.6 16

NOTE.Bz=Beuzyl radical; Cbz=Benzyloxycarbonyl radical.

In the same manner as described above, 4-N-benzyloxycarbonyl-PAMBA chloride melting at 85-88 C. was obtained from PAMBA. Yield 78.5%

EXAMPLE B-TRANS-4-N-TERTIALBUTYLOXY- CARBONYL-AMCHA CHLORIDE To 47.1 g. (0.3 mol) of trans-AMCHA dissolved in 300 ml. of 1 N-sodium hydroxide solution and 150 ml. of tetrahydrofurane, was added a syrup newly prepared and containing more than 0.33 mol. of tertialbutylcarbonylchloride (Bulletin of the Chemical Society of Japan, 38, 1522 (1965)) and 150 ml. of 2 N-sodium hydroxide solution over 30 min. with cooling with ice water and vigorous stirring. Stirring was continued for 1 hr. below 10 C. and for 30 min. at room temperature and then the mixture was neutraziled with l N-hydrochloric acid to pH 3 to precipitate white crystals, which were collected and recrystallized .from isopropylether to give 45.0 g. of trans- 4-N-tert-butyloxycarbonyl-AMCHA as white crystalline scales. M.P. 132-133 C. Yield 58.3%.

Elementary analysis for C H O N (M.W. 257.32) (percent): Calcd. C, 59.89; H, 8.89; N, 5.63. Found (percent): C, 60.54; H, 8.80; N, 5.63.

The thus obtained trans-4-N-tertbutyloxylcarbonyl- AMCHA (2.3 g.) and triethylamine (3.2 g.) were dis- What we claim is: 1. A compound of the general formula wherein Aryl is a phenyl, which may have one or more substituents selected from hydroxy, chlorine, bromine, nitro, amino, carboxyl, formyl, sulfamoyl, carboxy lower alkylamino, C to C -a1kyl, C to C alkoxy, C to C alkenyl, phenyl, carboxy lower alkoxy, carboxy lower alkenyl, hydroxy lower alkyl, lower alkoxycarbonyl and carboxy lower alkyl, the alkyl portion of which may be substituted with amino, hydroxy, chlorine or bromine, and the pharmaceutically acceptable salts thereof.

2. 4'-carboxyphenyl 4-aminomethyl-benzoate and the pharmaceutically acceptable salts thereof.

3. 4' carboxymethylphenyl 4-aminomethyl-benzoate and the pharmaceutically acceptable salts thereof.

4. 4' (2"-carboxyethyl)phenyl 4-aminomethylbenzoate and the pharmaceutically acceptable salts thereof.

5. 4' (2"-ca.rboxyvinyl)phenyl 4-aminomethyl-benzoate and the pharmaceutically acceptable salts thereof.

6. 4'-(2"-carboxyethoxy)phenyl 4-aminomethyl-benzoate and the pharmaceutically acceptable salts thereof.

'25 26 7. 4'-(5"-carboxy-n-pentyl)phenyl 4-aminomethyl-ben- References Cited zoate and the pharmaceutically acceptable salts thereof.

8. 4'-(1"-hydroxy-5"-carboxy-n-pentyl)phenyl 4-ami- UNITED STATES PATENTS nomethyl-benzoate and the pharmaceutically acceptable 3,342,301 9/ 1967 my 260-471 R salts thereof.

9. n sn y p yl)p y 4 amino. 5 A. Pnmary Examlner methyl-benzoate and the pharmaceutically acceptable salts L. A. THAX'ION, Assistant Examiner thereof.

10. 4' (2"-amino-2"-carboxyethyl)phenyl 4-amino- -S- C methyl-benzoate and the pharmaceutically acceptable salts 10 260 29 5 R 424 263 309 thereof.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3 793, 292 Dated February 19 1974- Inventor(s) Yuichi Yamamura et al It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

In the heading of the patent, insert:

-Claims Priority, applications Japan,

October 14, 1968 No. 74220/1968 December 12, 1968 No. 90564/l968- In the heading of the patent, the first name of inventor Hirata should read Miyoshi-.-

Signed and sealed this 6th day of August 1974.

(SEAL) Attest:

McCOY M. GIBSON, JR. Attesting Officer C. MARSHALL DANN Commissioner of Patents ORM po'wso USCOMM-DC wane-Poo U. 5. GOVERNMENT PRINTING OFFICE Z 1,, 3-3Jl. 

